title: Hyperglycemic levels of glucose inhibit interleukin 1 release from RAW 264.7 murine macrophages by activation of protein kinase C.
abstract: Diabetic patients with hyperglycemia (high blood glucose) have frequent and persistent bacterial infections linked to significantly diminished bactericidal activity and macrophage function. Interleukin-1 (IL-1), released primarily from activated macrophages, is a key mediator of effective host defense against microorganisms. We observe that hyperglycemic levels of D-glucose (8-20 mM) inhibit the release of IL-1 by lipopolysaccharide-stimulated RAW 264.7 murine macrophage cells. An inhibitor of glucose transport and metabolism, 2-deoxyglucose, prevents this inhibition of IL-1 release. High levels (8-20 mM) of fructose and mannose (but not galactose or L-glucose) also inhibit the release of IL-1 activity, suggesting that metabolism is required for IL-1 inhibition. Immunoprecipitation and activity measurements demonstrate that high glucose levels block the release of IL-1 but do not inhibit IL-1 production. High glucose levels (20 mM) increase protein kinase C (PKC) activity, and inhibitors of PKC block the inhibitory effects of glucose. Phorbol 12-myristate 13-acetate, an agonist of PKC, mimics glucose-induced inhibition of IL-1 release. These results demonstrate that high glucose levels inhibit IL-1 release (but not production) by RAW 264. 7 murine macrophages, and this inhibition is mediated by PKC activation. These studies suggest that persistent infections in hyperglycemic patients may be due to an inhibition of IL-1 release from macrophages.
authors.affiliation: Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Hill
authors.forename: G
authors.initials: G
authors.lastname: Kwon
authors.forename: C A
authors.initials: CA
authors.lastname: Marshall
authors.forename: M L
authors.initials: ML
authors.lastname: McDaniel
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001786:Blood Glucose / Q000378:metabolism*; D002460:Cell Line; D003847:Deoxyglucose / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051273:Glucose Transporter Type 2; D006943:Hyperglycemia / Q000097:blood*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D004791:Enzyme Inhibitors; D051273:Glucose Transporter Type 2; D007375:Interleukin-1; D009004:Monosaccharide Transport Proteins; D009569:Nitric Oxide; D003847:Deoxyglucose; D011493:Protein Kinase C